When a pathogen is able to infect a particular host there are varying levels of susceptibility. The subsequent infection may be transient in nature or it may continue to be a chronic infection. The pathogen may be cytopathic or non-cytopathic in the host organism. There may also be secondary manifestations of the infection that are not directly related to propagative processes of the pathogens themselves. For instance, a cytopathic virus can kill cells directly, but a non-cytopathic virus can indirectly kill cells by inducing a host immune response that is responsible for death of the infected cell. Other secondary manifestations can include inflammation, fibrosis, induced auto-immunity, apoptosis and cancer.
Due to the specific nature of some pathogens towards their host, there is a keen lack of appropriate animal model systems for testing therapeutic regimens for preventing, stabilizing or reversing some human disease manifestations. The art is also limited by the fact that in some systems, although there may be proliferation of the pathogen within the animal subject, the course of illness may be different from what is seen in a human subject. Presumably in these cases, the environment of the animal model is sufficiently different that key features of the disease seen in humans are not expressed. On the other hand and in contrast, there may be unique biological manifestations in the surrogate animal that are not seen in humans.
For instance, in cases where the host is not the natural host of a pathogen, the pathogen may be able to infect the cells or organs of the host but not be able to proliferate. An example of this would be HIV infection of macaques. Infection of these animals by the human virus HIV leads to low or unreproducible infection which is believed to be caused by a specific block in replication (Shibata et al., 1995, J Gen Virol; 76:2723). On the other hand, some viruses have a broad range of suitable hosts that can carry active infections from one species to another with rabies virus being a noted example. Although disease may be caused by replication of a pathogen, there may be other indirect or secondary manifestations that can be host specific. For instance, both humans and chimpanzees are able to be productively infected by HIV but the course of disease presentation is widely different between the two species since the chimpanzees lack the secondary manifestations that are expressed after infection of humans.
HBV is a pathogen that has been associated with secondary manifestations in humans. HBV has been shown to be able to infect a primitive primate, Tupaia belangeri, (Yan et al., 1996, described in related Ser. No. 08/876,635, filed on Jun. 16, 1997) but the correspondence of this infection with the disease process seen in humans has not been clear. Walter et al., 1996, also described in Ser. No. 08/876,635, reported that HBV infection of Tupaia is not analogous to the human disease in that there was only a very short, transient production of viral antigens without any evidence of chronic infection. Thus, the latter teaches away from the use of Tupaia as animal model systems that are analogous to infections of humans by HBV.
The limitations and disadvantages in the prior art field of animal models described above are overcome by the present invention as described below.